Relation between Genomic DNA Breakpoints in MLL Gene and Treatment Outcome in Infants with Acute Leukemia

LYMPHOID TUMORS , , ,

GA Tsaur1,2,3, C Meyer4, TO Riger1,2, AM Kustanovich5, EV Fleischman6, YuV Ol’shanskaya7, AM Popov7, OI Sokova6, EA Matveeva7, OV Nikulina1,2, AE Drui1,2, OR Arakaev1,2, OV Streneva1,2, SA Rumyantsev7, EV Shorikov1,2, AG Solodovnikov2, LI Savel’ev1,2, R Marschalek4, LG Fechina1

 1 Regional Children’s Clinical Hospital No. 1, 32 Serafimy Deryabinoi str., Ekaterinburg, Russian Federation, 620149

2 Research Institute of Medical Cell Technologies, 22a K. Marksa str., Ekaterinburg, Russian Federation, 620026

3 First President of Russia B.N. Yeltsin Ural Federal University , 19 Mira str., Ekaterinburg, Russian Federation, 620002

4 Diagnostic Center of Acute Leukemia, Institute of Pharmaceutical Biology/ZAFES, Goethe-University of Frankfurt, N230, Max-von-Laue Str. 9, Frankfurt am Main Deutschland, 60438

5 Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, 43 Frunzenskaya str., Borovlyany, Minsk District, Belarus, 223053

6 N.N. Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

7 Dmitrii Rogachev Federal Scientific Clinical Centre of Pediatric Hematology, Oncology and Immunology, 1 Samory Mashela str., Moscow, Russian Federation, 117198

For correspondence: Grigorii Anatol’evich Tsaur, PhD, 32 Serafimy Deryabinoi str., Ekaterinburg, Russian Federation, 620149; Tel.: +7(343)216-25-17; e-mail: tsaur@mail.ru

For citation: Tsaur GA, Meyer C, Riger TO, et al. Relation between Genomic DNA Breakpoints in MLL Gene and Treatment Outcome in Infants with Acute Leukemia. Clinical oncohematology. 2016;9(1):22–9 (In Russ).

DOI: 10.21320/2500-2139-2016-9-1-22-29

ABSTRACT

Aim. To evaluate the relation between genomic DNA breakpoints in MLL and translocation partner genes (TPG) and clinical parameters of infant AL.

Methods. 68 infants (29 boys and 39 girls with median age of 4.8 mo) with MLL-rearranged acute lymphoblastic leukemia (ALL) (n = 46), acute myeloid leukemia (AML) (n = 20) and mixed phenotype acute leukemia (MPAL) (n = 2) were included in the current study.

Results. 5-year EFS was significantly lower in patients with breakpoints in intron 11 (n = 29) in comparison to patients with breakpoint localized from intron 7 to exon 11 (n = 17) (0.16 ± 0.07 vs 0.38 ± 0.14, p = 0.039). While cumulative incidence of relapse was remarkably higher in the first group of patients (0.74 ± 0.09 vs 0.52 ± 0.17, p = 0.045). Although in Cox regression model including breakpoint location in intron 11 together with age, immunophenotype, initial white blood cell count, initial CNS involvement, type of MLL rearrangements, absolute blast number at day 8 of dexamethasone profase, minimal residual disease (MRD) at time point 4 (TP4) of MLL-Baby protocol, the only significant covariate was the presence of MRD at TP4 (HR 5.994, 95% CI 2.209–16.263, p < 0.001). In 22 AML patients there was not any correlation between breakpoint location and treatment outcome.

Conclusion. Breakpoints in intron 11 of MLL gene led to significantly worse outcome in infants with ALL, treated by MLL-Baby protocol, although this parameter was overcome by MRD-positivity at TP4. The latter was the only independent covariate in multivariate analysis. Our data provide additional information of molecular genetic features of MLL-rearranged infant AL.

Keywords: acute leukemia, infants, 11q23/MLL rearrangements, MLL-Baby, treatment outcome.

Received: September 14, 2015

Accepted: October 20, 2015

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